Acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus type-1 (HIV-1). When HIV-1 infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double-stranded viral DNA. The viral DNA is then integrated into the host chromosomal DNA, which then allows host cellular processes, such as transcription and translation to reproduce the virus. RTIs (reverse transcriptase inhibitors) block reverse transcriptase's enzymatic function and prevent completion of synthesis of the double-stranded viral DNA, thus preventing HIV from multiplying.
In the current treatment of HIV-1 infections, non-nucleoside reverse transcriptase inhibitors (NNRTIs) are very important in particular in drug combination therapies (highly active antiretroviral therapy or HAART) due to their unique antiviral activity. However, while NNRTIs (non-nucleoside reverse-transcriptase inhibitors) are effective at inhibiting DNA synthesis and HIV replication, HIV can develop mechanisms that confer the virus resistance to the drugs. HIV-1 reverse transcriptase does not have proof-reading activity, and this property combined with selective pressure from the drug inhibitors can lead to mutations in reverse transcriptase which makes the virus less susceptible to NNRTIs.
NNRTIs do not bind to the active site of the polymerase but in a less conserved pocket near the active site in the p66 subdomain. Their binding results in a conformational change in the reverse transcriptase that distorts the positioning of the residues, inhibiting polymerization. Mutations in response to first generation NNRTIs decrease the binding of these drugs in the pocket. There are three main mechanisms of NNRTI resistance:                a) the first NNRTI mutations disrupting the entry of the inhibitor to the NNRTI binding pocket is exemplified by the K103N and K101E mutations located at the entrance of the pocket, blocking the entrance/binding of the old generation drug in contrast to new generation drugs.        b) A second mechanism is the loss of important interactions on the inside of the pocket, exemplified by Y181C and Y188C mutations resulting in the loss of important π-π interactions between aromatic rings of the substrate and enzyme involved in NNRTI binding.        c) The third type of mutations can be involved in the size of the NNRTI binding pocket, creating a steric bulk in the pocket, leaving less room for an NNRTI to bind tightly, an example is the G190E mutation.        
Exemplary NNRTIs are diaryltriazines (DATA) (1-6) which are very potent NNRTIs and have anti-HIV-1 activity with nanomolar EC50 values against wild-type and single mutants. However, a problem with said prior art known DATA's is that they are less active or even ineffective against double and multiple HIV-1 mutants (1).
We have now discovered that by making use of suitable spacers in diaryltriazines, the compounds show an improved activity against double and multiple mutants compared to the corresponding triazines without spacer and prior art known diarylpyrimidines such as compound TMC120 (DAPY, Diarylpyrimidines). Dose-escalation studies making use of the compounds of the present application have shown a distinct mutational profile in comparison to NNRTI's, which are currently used in clinical management of HIV infection. This distinct mutational profile may potentially result in a clinical benefit since available therapy would not be compromised. This aspect makes this invention an important improvement compared to the current state of the art.
The present invention discloses compounds which differ from prior art compounds in structure and/or pharmacological activity.